This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The Redinbo group uses the tools of structural, molecular and chemical biology to examine dynamic cellular and systemic processes. We focus on four central areas: 1) Nuclear Receptors in transcriptional control and therapeutic development, 2) enzymes in chemotherapy and chemoprotection, 3) DNA manipulation machinery structure, function and inhibition, and 4) Bacterial pathogenesis. These areas overlap, for example we study DNA relaxases and helicases that catalyze the transfer of bacterial antibiotic resistance genes between bacterial cells;thus impacting area 3 &4. We study how the nuclear receptor PXR binds to xenobiotic chemicals that are foreign to the human body and promotes their inactivation, including anticancer drugs, thus impacting areas 1 &2. Our main goals are twofold: to advance the use of structural biology to inform how new therapeutics can be directed against bacterial infection, and to help design strategies to increase the lifetime of useful therapeutic compounds in the human body. The structures we target in this proposal will significantly impact these goals.